IL-2 (Interleukin-2) is a kind of cytokines, is produced mainly by activated T cells, and acts on the cells such as T cells, B cells, macrophages, etc. The IL-2 shows proliferation and activation of T cells, proliferation and acceleration of antibody-producing ability of B cells, activation of monocytes and macrophages, proliferation and activation of natural killer cells (NK cell), and inducing action of lymphokine-activated killer cells, etc. On the cell membrane of T cells, T cell antigen receptor (T Cell Receptor, TCR) is expressed, and T cells produce IL-2 by receiving antigen presentation from antigen presenting cells such as macrophages, etc.
It has been known that TCR existing on the surface of the T cell is being present by forming a complex with a molecule which is the so-called CD4. When an antigen is bound to TCR, phosphorylation of TCR is carried out by kinase in the cell. Phospholipase C (PLC) γ participates in release of calcium ion from endoplasmic reticulum, and activations of calmodulin and calcineurin are calcium-dependently induced. Calcineurin is to carry out dephosphorylation of a transcription factor NF-AT to transfer into a nucleus. Thereafter, NF-AT is bound to an IL-2 promotor, and production of IL-2 mRNA is accelerated.
Tacrolimus (FK506) and cyclosporine A which are immunosuppressants inhibit IL-2 production at the T cells. These drugs bind to cyclophilin and FK506-binding protein (FKBP) in the cells, and the complexes of the drug-protein bind to calcineurin. As stated above, calcineurin is an important molecule in transcriptional control of IL-2, and according to this mechanism, dephosphorylation of the calcineurin-dependent transcription factor NF-AT is inhibited, and as a result, an immunosuppressing action is expressed. These drugs have been mainly used for the purpose of suppressing rejection after organ transplantation. In addition, tacrolimus, etc., have also been used for the treatment of atopic dermatitis.
It has been reported that cytokines such as IL-2, etc., are deeply participated in bronchial asthma, etc. (Non-Patent Documents 1 to 2).
Further, it has been known that cytokine balance is participated in onset of rheumatoid arthritis, in particular, Th1 type cytokine such as IL-2, etc., plays a role of promoting onset of arthritis (Non-Patent Document 3).
In addition, production of IL-2 has been known to participate in the diseases such as AIDS, cancer, skin diseases (psoriasis, atopic dermatitis, urticaria), internal diseases (lupus nephritis), ophthalmic diseases (allergic conjunctivitis, sty, chalazion, spring catarrh, uveitis, cancer), autoimmune diseases (polymyositis, Hashimoto's disease, Behcet's disease, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, pollenosis, scleroderma), gastrointestinal diseases, inflammatory diseases (gout, psoriatic arthritis, rheumatoid arthritis), central nervous system diseases (multiple sclerosis), respiratory diseases (asthma, chronic obstructive pulmonary disease), fibromyalgia, myasthenia gravis, sarcoidosis, nasal inflammation, nasal catarrh, etc.
On the other hand, in JP Patent No. 4,296,345 (Patent Document 1), JP Patent No. 5061134 (Patent Document 2) and JP Patent No. 4360292 (Patent Document 3), it has been shown that some of 2-phenylbenzothiazoline derivatives have been specifically disclosed, and these act as a κ opioid receptor agonist, and are useful as a therapeutic agent and pain threshold decrease inhibitor of pain, pruritus, etc.
Also, (+)-3-acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline (−)-O,O′-diacetyl-L-tartarate which is one of the 2-phenylbenzothiazoline derivatives has been disclosed in European Journal of Pharmacology (2010), 647 (1-3), 62-67 (Non-Patent Document 4) and European Journal of Pharmacology (2011), 671 (1-3), 53-60 (Non-Patent Document 5), and shown that it has an antinociceptive action, an antipruritic action and a weak sedative action.
However, a relation between these 2-phenylbenzothiazoline derivatives and production of IL-2 has never been reported as of today, and it has never been known that the 2-phenylbenzothiazoline derivatives have an inhibiting action of IL-2 production as a matter of course.
FK506 and cyclosporine, and a steroidal anti-inflammatory drug also have an inhibiting action of IL-2 production. These medicaments have been used for various treatments, however, there are problems that potent side effects appears by administration for a long period of time, etc., and a safe medicament having high safety and effectiveness has not yet been found out. Therefore, it has been desired to develop a drug having a potent IL-2 production inhibiting action and safety.